CN109453199A - 间充质干细胞、组合物及注射液在制备治疗糖尿病药物的应用 - Google Patents
间充质干细胞、组合物及注射液在制备治疗糖尿病药物的应用 Download PDFInfo
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- CN109453199A CN109453199A CN201811308296.8A CN201811308296A CN109453199A CN 109453199 A CN109453199 A CN 109453199A CN 201811308296 A CN201811308296 A CN 201811308296A CN 109453199 A CN109453199 A CN 109453199A
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110438069A (zh) * | 2019-08-22 | 2019-11-12 | 石学高 | 一种连翘脂素用于体外促进人脂肪间充质干细胞成软骨分化的用途 |
CN113057967A (zh) * | 2019-12-16 | 2021-07-02 | 多能干细胞再生医学科技(广州)有限公司 | 一种治疗糖尿病的干细胞组合物及其制剂与用途 |
CN113995774A (zh) * | 2021-11-03 | 2022-02-01 | 博雅干细胞科技有限公司 | 细胞治疗剂及其治疗病毒性肺炎的用途 |
CN114042088A (zh) * | 2021-11-03 | 2022-02-15 | 博雅干细胞科技有限公司 | 治疗病毒性肺炎的细胞制剂 |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102066555A (zh) * | 2008-03-15 | 2011-05-18 | Smt.G.R.多斯及Smt.Km玛塔肾病研究所及研究中心 | 用于治疗糖尿病的源自人脂肪组织的胰岛素生产性间充质干细胞 |
WO2011116219A1 (en) * | 2010-03-17 | 2011-09-22 | Board Of Regent Of The University Of Texas System | Theranostic delivery systems with modified surfaces |
CN102920735A (zh) * | 2012-11-14 | 2013-02-13 | 青岛奥克生物开发有限公司 | 一种间充质干细胞注射液及其制备方法和在制备治疗糖尿病药物中的应用 |
CN106361771A (zh) * | 2016-11-08 | 2017-02-01 | 北京恒峰铭成生物科技有限公司 | 一种高糖激活的间充质干细胞注射液及其用于糖尿病药物的应用 |
CN107090431A (zh) * | 2017-03-31 | 2017-08-25 | 北京恒峰铭成生物科技有限公司 | 一种用于输注糖尿病的活性间充质干细胞注射液 |
CN108456655A (zh) * | 2018-02-23 | 2018-08-28 | 深圳至博生物科技有限公司 | 间充质干细胞悬浮液及其制备方法与应用 |
-
2018
- 2018-11-05 CN CN201811308296.8A patent/CN109453199A/zh active Pending
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102066555A (zh) * | 2008-03-15 | 2011-05-18 | Smt.G.R.多斯及Smt.Km玛塔肾病研究所及研究中心 | 用于治疗糖尿病的源自人脂肪组织的胰岛素生产性间充质干细胞 |
WO2011116219A1 (en) * | 2010-03-17 | 2011-09-22 | Board Of Regent Of The University Of Texas System | Theranostic delivery systems with modified surfaces |
CN102920735A (zh) * | 2012-11-14 | 2013-02-13 | 青岛奥克生物开发有限公司 | 一种间充质干细胞注射液及其制备方法和在制备治疗糖尿病药物中的应用 |
CN106361771A (zh) * | 2016-11-08 | 2017-02-01 | 北京恒峰铭成生物科技有限公司 | 一种高糖激活的间充质干细胞注射液及其用于糖尿病药物的应用 |
CN107090431A (zh) * | 2017-03-31 | 2017-08-25 | 北京恒峰铭成生物科技有限公司 | 一种用于输注糖尿病的活性间充质干细胞注射液 |
CN108456655A (zh) * | 2018-02-23 | 2018-08-28 | 深圳至博生物科技有限公司 | 间充质干细胞悬浮液及其制备方法与应用 |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110438069A (zh) * | 2019-08-22 | 2019-11-12 | 石学高 | 一种连翘脂素用于体外促进人脂肪间充质干细胞成软骨分化的用途 |
CN110438069B (zh) * | 2019-08-22 | 2022-11-22 | 深圳泽医细胞治疗集团有限公司 | 一种连翘脂素用于体外促进人脂肪间充质干细胞成软骨分化的用途 |
CN113057967A (zh) * | 2019-12-16 | 2021-07-02 | 多能干细胞再生医学科技(广州)有限公司 | 一种治疗糖尿病的干细胞组合物及其制剂与用途 |
CN113995774A (zh) * | 2021-11-03 | 2022-02-01 | 博雅干细胞科技有限公司 | 细胞治疗剂及其治疗病毒性肺炎的用途 |
CN114042088A (zh) * | 2021-11-03 | 2022-02-15 | 博雅干细胞科技有限公司 | 治疗病毒性肺炎的细胞制剂 |
CN113995774B (zh) * | 2021-11-03 | 2023-08-11 | 博雅干细胞科技有限公司 | 细胞治疗剂及其治疗病毒性肺炎的用途 |
CN114042088B (zh) * | 2021-11-03 | 2023-11-07 | 博雅干细胞科技有限公司 | 治疗病毒性肺炎的细胞制剂 |
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